| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
PTEN, atumor suppressor gene,is essential for embryogenesis.
We used the Cre-1oxP system to generate a T. cell-specific deletion of the Pten gene (LckCrePten^<flox/-> (Pten^<flox/->)mice). All Pten^<flox/-> mice developed CD4^+ T cell lymphomas by 17 weeks. Pten^<flox/-> mice showed increased thymic cellularity due in part to a defect in thymic negative selection. Pten^<flox/-> mice exhibited elevated levels of B cells and CD4^+ T cells in the periphery, spontaneous activation of CD4^+ T cells, autoantibody production, and hyperimmunbglobuhnemia. Pten^<flox/-> T cells hyperproliferateed, were autoreactive, secreteed increased levels of Th1/Th2 cytoianes, resisted apoptosis and showed increased phosphorylation of PKB/Akt. Peripheral tolerance to SEB was also impaired in Pten^<flox/-> mice. PTEN is thus an important regulator of T cell homeostasis and selftolerance.
We also generated a B cell-specific null mutation of Pten in mice (CD19CrePten^<flox/flox> (bPten^<flox/flox>) mice). bPten^<
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flox/flox> mice showed a marked accumulation of B la cells and increased levels of serum autoantibodies. Among B2 cells in bRen^<flox/flox> spleens, numbers of marginal zone B (MZB) cells were significantly increased while those of follicular B (FOB) cells were correspondingly decreased. Pten-deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and showed enhanced migration. The survival kinase PKB/Akt was highly activated in Pten-deficient splenic B cells. In addition, bPten^<flox/flox> mice exhibited a defect of immunoglobulin class switch recombination that may have been associated with impaired induction of activation-induced cytidine deaminase (AID). Thus, Pten plays a role in developmental fate determination of B cells and is an indispensable regulator of B cell homeostasis.
To investigate the function of Pten in non-lymphoid cells, we first examine the differentiation of Pten defective ES cells into hematopoietic cells by op9 system. Pten defective ES cells showed significant impairment of differentiation into hematopoietic cells. We are now trying to establish other Pten defective ES cell lines to confirm whether the difference is really significant or not.
We also generated a hematopoietic stem cell-specific null mutation of Pten in mice (Tie2Cre Pten^<flox/flox> mice).These mice are embryonic lethal. We are now trying to analyze whether the lethality is due to hematopoietic disorder or not. Less
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